Kaposi's sarcoma, a common AIDS-associated neoplasm, has been correlated with the infection and replication of a recently identified human herpesvirus (HHV-8). HHV-8, also known as Kaposi's sarcoma-associated herpesvirus (KSHV), requires the activity of a virally encoded protease (KSHV Pr) for its maturation in vivo and in cell culture. This protease appears to utilize structural and substrate recognition motifs quite different from other serine proteases, such as those of the chymotrypsin and subtilisin families. These latter classes of enzymes have been extensively studied by the Craik group; such previous knowledge and experience should aid in elucidation of the molecular details of KSHV Pr's structure, substrate recognition, and catalytic mechanism. Structural studies are currently underway with KSHV Pr, aided by the resources of CGL. This variant enzyme is currently being used to determine the three-dimensional structure of KSHV Pr. This effort will in turn aid in the structure-based design of small molecule protease inhibitors and the rational selection of dominant-negative KSHV Pr species. The resources of CGL are invaluable in this course of study and will continue to contribute to the development of possible pharamacuetical strategies to intervene in the KSHV life cycle.